Matsushiro Domain (松代藩 Matsushiro-han?) was a feudal domain under the Tokugawa shogunate of Edo period Japan. It is located in Shinano Province, Honshū. The domain was centered at Matsushiro Castle, located in what is now part of the city of Nagano in Nagano Prefecture.
Kawanakajima in northern Shinano Province was the site of numerous battles in the Sengoku period between Takeda Shingen and Uesugi Kenshin. After the start of the Tokugawa shogunate, this area was awarded as a domain to Mori Tadamasa for his efforts in the Battle of Sekigahara by Tokugawa Ieyasu. The marked the start of the 137,000 koku Kawanakajima Domain. Mori was transferred three years later to Tsuyama Domain in Mimasaka Province in 1603. The domain was then awarded in 1610 to Matsudaira Tadateru, the 6th son of Tokugawa Ieyasu; however, he was dispossessed in 1606 and the domain was suppressed.
In 1616, Matsudaira Tadamasa, the son of Yūki Hideyasu was awarded a 130,000 koku holding in northern Shinano, and chose Matsushiro as the location for his castle. The marked the start of Matsushiro Domain. He was transferred to Takada Domain in Echigo Province after only three years, and the domain went to Sakai Tadakatsu, who was in turn transferred to Shonai Domain in Dewa Province in 1622.